1. Field of the Invention
The present invention relates generally to the synthesis of heterocyclic compounds based on the tricyclic tetrahydroquinoline ring. More specifically, the invention provides novel tricyclic tetrahydroquinolines as well as novel libraries comprised of such compounds.
2. Background Information
The process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested one or more structure(s) is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional one-at-a-time synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional one-at-a-time synthesis methods, except over a time frame of months or even years. Faster methods are needed that allow for the preparation of up to thousands of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as tricyclic tetrahydroquinolines.
Solid-phase techniques for the synthesis of peptides have been extensively developed and combinatorial libraries of peptides have been generated with great success. During the past four years there has been substantial development of chemically synthesized combinatorial libraries (SCLs) made up of peptides. The preparation and use of synthetic peptide combinatorial libraries has been described, for example, by Dooley in U.S. Pat. No. 5,367,053, Huebner in U.S. Pat. No. 5,182,366, Appel et al. in WO PCT 92/09300, Geysen in published European Patent Application 0 138 855 and Pirrung in U.S. Pat. No. 5,143,854. Such SCLs provide the efficient synthesis of an extraordinary number of various peptides in such libraries and the rapid screening of the library which identifies lead pharmaceutical peptides.
Combinatorial approaches have recently been extended to "organic" or non-peptide, libraries. The organic libraries to the present, however, are of limited diversity and generally relate to peptidomimetic compounds; in other words, organic molecules that reta in peptide chain pharmacophore groups similar to those present in the corresponding peptide.
Combinatorial chemical methods have bee n applied to a limited number of heterocyclic compounds, as described, for example, in U.S. Pat. No. 5,288,514 to Ellman, U.S. Pat. No. 5,324,483 to Cody et al. and Goff and Zuckermann, J. Org. Chem., 60:5748-5749 (1995). Additionally, there is U.S. Pat. No. 5,549,974 to Holmes and U.S. Pat. No. 5,506,337 to Summerton and Weller. However, the heterocyclic libraries to d at e contain compounds of limited diversity and complexity.
Five 3,4-cyclopentenyl substituted tetrahydroquinolines have Grieco and Bahsas, Tetrahedron Letters, 29:5855-5858 (1988). However, their procedures are limited to use of one equivalent of aldehyde for formation of the imine intermediate in order to limit the hetero Diel-Alder reaction with cyclopentadiene and thus avoid a double hetero Diels-Alder reaction. Gregoire et al., Tetrahedron Letters, 32:7099 (1991), has also described classical synthesis of the cyclopentadiene hetero Diels-Alder reaction to prepare a series of nine aza-steroid derivatives. There remains a need, however, to prepare these compounds in libraries of substantial molecular diversity.
Patent application WO 94/08051 discloses the reaction of ether-linked aldehyde-derived imines with dihydrofuran under Lewis acid catalysis.
However, the library described therein was limited to 108 compounds.
Moreover, while lanthanide triflates have been reported to effect the preparation of tricyclic tetrahydroquinolines they are expensive and the reaction scope where they have been employed is very limited. See for example, Kobayashi et al., Chemistry Letters, 423 (1995).
Substituent limitations have been overcome for mixtures of peptides and peptidomimetics through the use of solid phase techniques versus solution-phase. An important step in the development of solid-phase techniques was the discovery of methods to identify active individual compounds from soluble mixtures of large numbers of compounds, as described, for example, by Rutter in U.S. Pat. No. 5,010,175 and Simon in WO PCT 91/19735. These soluble mixture methods, however, have rarely been applied to the syntheses of complex heterocyclic structures. There exists a need to develop more complex "organic" libraries based on heterocyclic medicinal compounds which would require less time and effort in the synthesis and testing needed to bring an organic pharmaceutical product to fruition. In short, improved methods for generating therapeutically useful heterocyclic compounds, such as tricyclic tetrahydroquinoline derivatives, are desired.
This invention satisfies these needs and provides related advantages as well. The present invention overcomes the known limitations to classical organic synthesis of tricyclic tetrahydroquinolines and as well as the shortcomings of combinatorial chemistry with heterocycles. The present invention combines the techniques of solid-phase synthesis of heterocycles and the general techniques of synthesis of combinatorial libraries to prepare new tricyclic tetrahydroquinoline compounds.